Diagnostic agents for positron emission imaging using radiolabeled halogenated xanthenes

Patent 7427389 Issued on September 23, 2008. Estimated Expiration Date:

February 3, 2025. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.

Abstract Claims Description Full Text

Patent References

Method for diagnosis of atherosclerosis
Patent #: 4577636
Issued on: 03/25/1986
Inventor: Spears

Cleavable linkers for the reduction of non-target organ retention of immunoconjugates
Patent #: 5171563
Issued on: 12/15/1992
Inventor: Abrams, et al.

Image enhancement by coadministration of biomodulators and structurally modified imaging agents
Patent #: 5240693
Issued on: 08/31/1993
Inventor: Born, et al.

Method for improved imaging and photodynamic therapy Patent #: 6493570
Issued on: 12/10/2002
Inventor: Dees, et al.

Inventors

Assignee

Provectus Pharmatech, Inc.

Application

No. 11049797 filed on 02/03/2005

US Classes:

424/1.89, Fluorine424/1.11, RADIONUCLIDE OR INTENDED RADIONUCLIDE CONTAINING; ADJUVANT OR CARRIER COMPOSITIONS; INTERMEDIATE OR PREPARATORY COMPOSITIONS424/1.65, In an organic compound424/1.81, Nonmetal radionuclide or intended radionuclide (e.g., carbon)424/1.85, Halogen424/9.4, X-ray contrast imaging agent (e.g., computed tomography, angiography, etc.)424/9.1, IN VIVO DIAGNOSIS OR IN VIVO TESTING424/9.45, Halogenated benzene ring containing424/9.451Two or more halogenated benzene rings in the same compound

Examiners

Primary: Jones, D. L.

Attorney, Agent or Firm

Cook Alex Ltd.

Foreign Patent References

846674 GB 08/01/1960

International Classes

A61K 51/00
A61M 36/14

Description

BACKGROUND OF THE INVENTION

The present invention is directed to new diagnostic agents, and methods of use of such agents, for medical imaging using positron emission tomography (PET). PET is a nuclear medicine imaging technique which produces a three dimensional image ofthe body. PET imaging is commonly used to obtain non-invasive information about internal body structures and tissues and the function and health of such structures and tissues. PET uses a metabolically active molecule and a short-lived radioactivetracer isotope (to radiolabel the active molecule) as a diagnostic agent. The isotope decays by emitting a positron. When a PET diagnostic agent is administered to the body, it is retained or accumulates in certain tissues of interest, therebyfacilitating imaging of those tissues based upon detection of gamma ray photons produced upon annihilation of positrons emitted from the radiolabeled PET diagnostic agent. Such annihilation occurs when an emitted positron collides with an electronpresent in the vicinity of emission, resulting in production of two 511 keV photons that are emitted in nearly opposite directions. Typically, such PET diagnostic agents are radiolabeled with (i.e., contain) one or more atoms that exhibit positronemission (such as certain isotopes of carbon, nitrogen, oxygen, fluorine, or rubidium, including ^11C, ^13N, ^15O, ^18F, and ^82Rb). The effects of the emitted positrons (i.e., the subsequently emitted gamma ray photons) are detectedby a detection device located outside the body which typically converts raw data into two- or three-dimensional images of the region of interest. The results are then read by a nuclear medicine physician or radiologist to interpret the results in termsof the patient's diagnosis and treatment.

Considerable effort has been invested in development of PET diagnostic agents in an effort to improve contrast between various anatomical features, such as between cancerous and non-cancerous tissues. Continued progress in medical sciencemandates improved options in such diagnostic capability, which in turn mandates further development of improved diagnostic agents.

Therefore, it is one object of the present invention to meet these characteristics, to overcome the drawbacks in prior methods and agents and to provide an improvement over these prior methods and agents.

SUMMARY OF THE INVENTION

The present invention is directed to certain diagnostic agents for PET imaging and methods for using such agents exhibiting positron emission.

In a preferred embodiment, a primary component of such diagnostic agent is a halogenated xanthene or a functional derivative of a halogenated xanthene that has been radiolabeled with one or more positron emitting isotopes of carbon, oxygen,fluorine, chlorine, bromine, or iodine, including ^10C, ^11C, ^13O, ^14O, ^15O, ^17F, ^18F, ^32Cl, ^33Cl, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I, ^118I, ^119I, ^120I,^121I, ^122I, ^124I, ^126I, and ^128I. In a further preferred embodiment, this radiolabeled halogenated xanthene is Rose Bengal or a functional derivative of Rose Bengal.

These invented agents can be used in a method for imaging human or animal tissue comprising the steps of:

administering a diagnostic agent to a patient, a portion of said diagnostic agent being retained in tissue of interest, said diagnostic agent emitting positrons; and

imaging said tissue based on the effects of said positrons emitted from the diagnostic agent,

wherein said diagnostic agent is a radiolabeled halogenated xanthene.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is an illustration of the chemical structure of a halogenated xanthene; and

FIG. 1b is an illustration of the chemical structure of Rose Bengal.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENT

The present invention is directed to certain diagnostic agents for PET imaging and methods for using such agents exhibiting positron emission. In a preferred embodiment, a primary component of such diagnostic agent is a halogenated xanthene or afunctional derivative of a halogenated xanthene that has been radiolabeled with one or more positron emitting isotopes of carbon, oxygen, fluorine, chlorine, bromine, or iodine, including ^10C, ^11C, ^13O, ^14O, ^15O, ^17F,^18F, ^32Cl, ^33Cl, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I, ^118I, ^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and ^128I. In a further preferred embodiment, this radiolabeledhalogenated xanthene is Rose Bengal (i.e., 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) or a functional derivative of Rose Bengal.

The halogenated xanthenes constitute a family of extremely useful agents that can be selectively and safely delivered at high concentrations to certain tissues. Certain properties of the halogenated xanthenes are described in U.S. Ser. No.09/184,388, filed on Nov. 2, 1998, in U.S. Ser. No. 09/216,787, filed on Dec. 21, 1998, in U.S. Ser. No. 09/635,276, filed on Aug. 9, 2000, in U.S. Ser. No. 09/799,785, filed on Mar. 6, 2001, in U.S. Ser. No. 09/817,448, filed on Mar. 26,2001, in U.S. Ser. No. 09/900,355, filed on Jul. 6, 2001, and in U.S. Ser. No. 10/314,840, filed on Dec. 9, 2002, which are herein incorporated by reference in their entirety. In general, the halogenated xanthenes are characterized by a lowcytotoxicity (toxicity to cells) at low concentration, a propensity for selective concentration or retention in certain tissues and cells, a high cytotoxicity upon such concentration or retention, and by chemical and physical properties that aresubstantially unaffected by the local chemical environment or by the attachment of functional derivatives at positions R¹ and R² described below.

The generalized chemical structure of the halogenated xanthenes is illustrated in FIG. 1a, where the symbols X, Y, and Z represent various elements present at the designated positions, and the symbols R¹ and R² represent variousfunctionalities present at the designated positions. The chemical structure of a specific example of a halogenated xanthene, Rose Bengal, is illustrated in FIG. 1b. Physical properties of representative halogenated xanthenes are summarized in attachedTable 1. In general, the halogenated xanthenes have the empirical formula, C_{20H.sub.nO.sub.5F.sub.aCl.sub.bBr.sub.cI.sub.d},R¹,R², where n≥2, and a, b, c, and d are integers greater than or equal to zero. For example, the empiricalformula for the disodium salt of Rose Bengal is C_{20H.sub.2O.sub.5F.sub.0Cl.sub.4Br.sub.0I.sub.4},R¹,R.- sup.2, where R¹ and R² each represent a sodium atom, or, more simply, C_{20H.sub.2O.sub.5Cl.sub.4I.sub.4},Na_2.

Moreover, the facility with which the halogenated xanthenes target specific tissues or other sites can be further optimized by attachment of specific functional derivatives at positions R¹ and R², so as to change the chemicalpartitioning and/or biological activity of the agent. For example, attachment of one targeting moiety or more at positions R¹ or R² can be used to improve targeting to specific tissues, such as cancerous tumor tissues or sites of localizedinfection. An example of this is esterification at position R¹ with a short aliphatic alcohol, such as n-hexanol, to produce a derivatized agent exhibiting enhanced partitioning into lipid-rich tumor tissues.

It is thus a further preferred embodiment that at least one of the at least one halogenated xanthene active ingredients includes at least one targeting moiety selected from a group that includes deoxyribonucleic acid (DNA), ribonucleic acid(RNA), amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors, carbohydrate complexing agents, lipid receptors, lipid complexing agents, protein receptors, protein complexing agents, chelators, short-chain aliphatic hydrocarbons,long-chain aliphatic hydrocarbons, and aromatic hydrocarbons.

In their non-radiolabeled form, the halogenated xanthenes are useful as food dyes, biological stains, photosensitizers (i.e. agents which are used with light for photodynamic imaging or treatment as for example disclosed in U.S. Ser. Nos. 09/635,276 and 09/799,785), radiosensitizers (i.e., agents that are used with applied ionizing radiation for imaging and radiation treatment as for example disclosed in U.S. Ser. Nos. 09/216,787 and 09/817,448), and as chemoablative orchemotherapeutic agents (as for example disclosed in U.S. Ser. No. 09/900,355). When labeled with certain gamma-emitting isotopes of iodine (i.e., ^131I and ^125I), one of the halogenated xanthenes (Rose Bengal) has proven useful for diagnosisof hepatic function based on either measurement of differential excretion or imaging of the pattern of gamma emission from such radiolabeled molecules (for example as disclose in Serafini et al., J. Nucl. Med. 16 (1975) 629-633).

The present inventors were part of a team that has previously discovered and disclosed that the halogenated xanthenes exhibit selective retention in certain types of tissue, especially those exhibiting cancerous or precancerous conditions (i.e.,neoplasia, dysplasia, and hyperplasia), as disclosed in U.S. Ser. Nos. 09/635,276, 09/799,785, 09/216,787, 09/817,448, and 09/900,355. Such retention can be useful for diagnosis (for example, using x-ray computed tomography or ultrasound imaging) andfor therapy (for example, using photodynamic therapy or radiosensitization).

The present inventors have now discovered new isotopically-labeled (i.e., radiolabeled) members of the halogenated xanthene family that are capable of serving as diagnostic agents for PET imaging. More specifically, Applicants have created newhalogenated xanthene compounds wherein a halogenated xanthene or a functional derivative of a halogenated xanthene has been radiolabeled with one or more positron emitting isotope of carbon, oxygen, fluorine, chlorine, bromine, or iodine, including^10C, ^11C, ^13O, ^14O, ^15O, ^17F, ^18F, ^32Cl, ^33Cl, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I, ^118I, ^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and^128I. One skilled in the art can synthesize and produce these new compounds using known chemistry of the halogenated xanthenes with the additional information provided in this application. For example, the synthesis and production ofnon-radiolabeled halogenated xanthenes and the chemistry of such compounds is known. Labeling with radioisotopes, such as for example the preferred radioisotopes of bromine or iodine (i.e., ^74Br, ^75Br, ^76Br, ^77Br, ^78Br,^117I, ^118I, ^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and ^128I), can be achieved by using standard halogen exchange methods, such as those taught in Serafini, supra. For these radioisotopes and the otherradioisotopes listed herein, radiolabeling can be achieved using radiolabeled starting materials in the synthesis of the desired halogenated xanthene (such as for example radiolabeled resorcinol or a radiolabeled phthalic anhydride), thereby directlysynthesizing the radiolabeled xanthene.

The present inventors have further discovered that a halogenated xanthene or a functional derivative of a halogenated xanthene that has been radiolabeled with one or more positron emitting isotope of carbon, oxygen, fluorine, chlorine, bromine,or iodine, including ^10C, ^11C, ^13O, ^14O, ^15O, ^17F, ^18F, ^32Cl, ^33Cl, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I, ^118I, ^119I, ^120I, ^121I, ^122I,^124I, ^126I, and ^128I, can be useful as the active substance in a diagnostic agent for PET imaging. This non-naturally-occurring, novel composition of matter will retain the desirable specificity, toxicity, and other salient pharmaceuticalproperties of the halogenated xanthenes, as discussed above. Some of the important physical properties of the preferred positron emitting isotopes of carbon, oxygen, fluorine, chlorine, bromine, and iodine are summarized in attached Table 2. Becausepositron emitting isotopes with very short half-lives may in general be impractical for use in diagnostic procedures due to logistic difficulties in their timely production and subsequent delivery to the patient, those isotopes exhibiting half-lives inexcess of approximately one minute are preferred and are more useful. These preferred longer-lived positron emitting isotopes include ^11C, ^15O, ^18F, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I, ^118I,^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and ^128I. Because the distance traveled by the emitted positron prior to annihilation adversely affects image resolution (where traveled distance is proportional to positron energy),those longer-lived isotopes emitting lower energies are more preferred. Hence, the more preferred longer-lived, lower-energy positron emitting isotopes include ^11C, ^18F, ^75Br, ^77Br, ^121I, ^124I, and ^126I.

Thus, a diagnostic agent containing a halogenated xanthene radiolabeled with one or more of the aforementioned positron emitting elements can be used as a diagnostic agent for PET.

Hence, one preferred embodiment of the present invention is a diagnostic agent that contains, as an active ingredient at a concentration of from greater than approximately 0.001% to less than approximately 20%, at least one halogenated xantheneradiolabeled with one or more positron emitting isotope selected from the group of ^10C, ^11C, ^13O, ^14O, ^15O, ^17F, ^18F, ^32Cl, ^33Cl, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I,^118I, ^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and ^128I (i.e., a radiolabeled halogenated xanthene). It is further preferred that this radiolabeled halogenated xanthene is radiolabeled with one or more longer-livedpositron isotope selected from the group of ^11C, ^15O, ^18F, ^34Cl, ^74Br, ^75Br, ^76Br, ^77Br, ^78Br, ^117I, ^118I, ^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and ^128I. It isfurther preferred that this radiolabeled halogenated xanthene is radiolabeled with one or more longer-lived, lower-energy positron emitting isotopes selected from the group of ^11C, ^18F, ^75Br, ^77Br, ^121I, ^124I, and ^126I.

It is further preferred that this radiolabeled halogenated xanthene is radiolabeled Rose Bengal.

Examples of radiolabled halogenated xanthenes which can be used in the diagnostic agent of the present invention include one or more of the following:

radiolabeled 4',5'-Dichlorofluorescein;

radiolabeled 2',7'-Dichlorofluorescein;

radiolabeled 4,5,6,7-Tetrachlorofluorescein;

radiolabeled 2',4',5',7'-Tetrachlorofluorescein;

radiolabeled Dibromofluorescein;

radiolabeled Solvent Red 72;

radiolabeled Diiodofluorescein;

radiolabeled Eosin B;

radiolabeled Eosin Y;

radiolabeled Ethyl Eosin;

radiolabeled Erythrosin B;

radiolabeled Phloxine B;

radiolabeled Rose Bengal;

radiolabeled 4,5,6,7-Tetrabromoerythrosin;

radiolabeled Mono-, Di-, or Tribromoerythrosin;

radiolabeled Mono-, Di-, or Trichloroerythrosin;

radiolabeled Mono-, Di-, or Trifluoroerythrosin;

radiolabeled 2',7'-Dichloro-4,5,6,7-Tetrafluorofluorescein;

radiolabeled 2',4,5,6,7,7'-Hexafluorofluorescein;

radiolabeled 4,5,6,7-Tetrafluorofluorescein,

radiolabeled 2',4',5,5',6,7'-Hexaiodofluorescein;

radiolabeled 2',4',5,5',7,7'-Hexaiodofluorescein;

radiolabeled 2',4',5',6,7,7'-Hexaiodofluorescein;

radiolabeled 2',4',5,5',6,7,7'-Heptaiodofluorescein;

radiolabeled 4-Chloro-2',4',5,5',6,7'-hexaiodofluorescein;

radiolabeled 4-Chloro-2',4',5,5',7,7'-hexaiodofluorescein;

radiolabeled 4-Chloro-2',4',5',6,7,7'-hexaiodofluorescein;

radiolabeled 4-Chloro-2',4',5,5',6,7,7'-heptaiodofluorescein;

radiolabeled 4,5-Dichloro-2',4',5',6,7,7'-hexaiodofluorescein;

radiolabeled 4,6-Dichloro-2',4',5,5',7,7'-hexaiodofluorescein; and

radiolabeled 4,7-Dichloro-2',4',5,5',6,7'-hexaiodofluorescein,

wherein said radiolabel comprises incorporation of one or more positron emitting isotope selected from the group of ^10C, ^11C, ^13O, ^14O, ^15O, ^17F, ^18F, ^32Cl, ^33Cl, ^34Cl, ^74Br, ^75Br,^76Br, ^77Br, ^78Br, ^117I, ^118I, ^119I, ^120I, ^121I, ^122I, ^124I, ^126I, and ^128I.

In an alternate preferred embodiment, positron emission tomography is used to image, detect or otherwise observe the presence of a diagnostic agent that contains, at a concentration of from greater than approximately 0.001% to less thanapproximately 20%, at least one radiolabeled halogenated xanthene. It is further preferred that this diagnostic agent include the radiolabeled form of the halogenated xanthene Rose Bengal.

This description has been offered for illustrative purposes only and is not intended to limit the invention of this application.

TABLE-US-00001 TABLE 1 Physical properties of some example halogenated xanthenes (non-radiolabeled). Substitution MW Compound X Y Z R¹ R² (g) 4',5'-Dichlorofluorescein Cl H H Na Na 445 2',7'-Dichlorofluorescein H Cl H Na Na 4454,5,6,7-Tetrachlorofluorescein H H Cl H H 470 2',4',5',7'-Tetrachlorofluorescein Cl Cl H Na Na 514 Dibromofluorescein Br H H Na Na 534 Solvent Red 72 H Br H H H 490 Diiodofluorescein I H H Na Na 628 Eosin B NO₂ Br H Na Na 624 Eosin Y Br Br H Na Na692 Ethyl Eosin Br Br H C_2H.sub.5 K 714 Erythrosin B I I H Na Na 880 Phloxine B Br Br Cl Na Na 830 Rose Bengal I I Cl Na Na 1018 4,5,6,7-Tetrabromoerythrosin I I Br Na Na 1195

TABLE-US-00002 TABLE 2 Isotopes of relevance for PET with the halogenated xanthenes. Positron Emission Emission Energy Element Isotope Half-Life (MeV) Carbon ^10C 19 sec 1.9 ^11C 20 min 1.0 Oxygen ^13O 0.009 sec 6.4 ^14O 71 sec1.8 ^15O 124 sec 1.7 Fluorine ^17F 66 sec 1.7 ^18F 110 min 0.6 Chlorine ^32Cl 0.3 sec 9.5 ^33Cl 2.5 sec 4.5 ^34Cl 32 min 2.5 Bromine ^74Br 36 min 4.7 ^75Br 1.7 hours 0.3 ^76Br 16.1 hours 1.2-3.6 ^77Br 57 hours 0.4^78Br 6.4 min 1.9 Iodine ^117I 7 min ^118I 14 min 5.5 ^119I 19 min ^120I 1.3 hours 2.1-4.0 ^121I 2.1 hours 1.2 ^122I 3.5 min 1.8-3.1 ^124I 4.2 days 0.8-2.1 ^126I 13 days 1.1 ^128I 25 min

What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims.